EP0575321A1 - Synergistische Tumortherapie durch Kombinationen von Biologisch-aktiven anti-Tumor Antikörpern und Chemo Therapie - Google Patents
Synergistische Tumortherapie durch Kombinationen von Biologisch-aktiven anti-Tumor Antikörpern und Chemo TherapieInfo
- Publication number
- EP0575321A1 EP0575321A1 EP91910573A EP91910573A EP0575321A1 EP 0575321 A1 EP0575321 A1 EP 0575321A1 EP 91910573 A EP91910573 A EP 91910573A EP 91910573 A EP91910573 A EP 91910573A EP 0575321 A1 EP0575321 A1 EP 0575321A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- antibody
- antibodies
- tumor
- chemotherapy
- treatment
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to the use of combinations of antibody therapy and chemotherapy in the treatment of malignant disease. It is based, in part, on the surprising discovery that patients previously unresponsive to standard chemotherapy regimens achieved complete remission when treated with a combination regimen comprising treatment with anti-tumor antibody as well as chemotherapy.
- the methods of the invention provide a unique means for marshalling a patient's immune system to act in concert with exogenous chemical compounds to effectively eradicate tumor cells.
- Tumor cells express certain antigens which are absent from, or present in small amounts on, their normal cellular counterparts. Most of these are differentiation antigens, shared by the tumor and certain embryonic cells. Some of the antigens that appear with sufficient selectivity in tumors may serve as possible targets for therapeutic agents. This has been recently reviewed for malignant melanoma, which is one of the human tumors most studied in this respect (Hellstrom and Hellstrom, in Accomplishments in Cancer Research-194 Prize Year, General Motors Cancer Research Foundation, J. G. Fortner & J. E. Rhoads, eds., J. B. Lippincott Company, Philadelphia 1985, p.
- Attractive approaches for preparing anti-cancer agents involve labeling antibodies with radioactive isotopes (Larson et al., 1983, J. Clin. Invest. 72: 2101-2114; Order, 1984, Compr. Ther. 10: 9-18; Carrasquillo et al., 1984, Cancer Treatment Reports 68: 317-328; de Nardo et al. 1985, Int. J. Radiation Oncology Biol. Phys. 11: 335-348), or conjugating antibodies to toxins (Jansen et al., 1982, Immunol. Rev.
- the present invention relates to the use of combinations of antibody therapy and chemotherapy in the treatment of malignant disease. It is based in part, on observations of the surprising effectiveness of combination therapy; several patients who had received the anti-tumor antibody L6 or MG21 achieved complete remission in response to subsequent chemotherapy, although the same patients had not responded to similar chemotherapy regimens prior to receiving L6 or MG21 antibody treatment.
- anti- glycolipid antibodies such as, preferably, L6 monoclonal antibody or MG21 monoclonal antibody
- chemotherapy is administered within several months of antibody treatment. It is suggested that the effectiveness of combination therapy can be attributable to antibodies at the tumor site which render the malignant cells more susceptible to the toxic effects of chemotherapeutic agents or induce an immune response in a patient that synergizes with the chemotherapy drugs. 4. DETAILED DESCRIPTION OF THE INVENTION
- the present invention relates to therapeutic regimens comprising treatment with anti-tumor antibodies and standard chemotherapy.
- the anti-tumor antibodies react with glycolipid antigens on the surface of tumor cells.
- the anti-tumor antibody is the monoclonal antibody L6 or the monoclonal antibody MG21.
- the anti-tumor antibodies L6 and MG21 are present at the tumor site weeks after administration. By binding to the surface of tumor cells, the antibodies may render the cells more susceptible to chemotherapeutic killing, possibly by increasing drug uptake.
- treatment with anti-tumor antibody may induce an immune response in patients which synergizes with the chemotherapy drugs, either by making the cells more sensitive to the drugs or by making the cells more sensitive to the patient's immune response.
- Antibodies of virtually any origin can be used according to the present invention, but in preferred embodiments the antibodies define a tumor-associated antigen, such as a glycolipid antigen, a glycoprotein antigen, or mucin.
- a tumor-associated antigen such as a glycolipid antigen, a glycoprotein antigen, or mucin.
- Monoclonal antibodies offer the advantage of.a continuous, ample supply. In fact, by immunizing mice with tumor-associated glycolipid antigens establishing hybridomas making antibodies to such antigens it should be possible to rapidly establish a panel of antibodies capable of reacting with and treating a large variety of human tumors.
- the MG21 antibody is also described in copending U.S. application serial number 834,162 filed February 20, '°1986 which is incorporated by reference herein.
- the L6 antibody and the antigen it defines are described more fully in copending U.S. application Serial No. 684,759, filed December 21, 1984 and in U.S. Patent No. 4,906,562, filed October 18, 1985 which are each incorporated by reference herein.
- monoclonal antibodies can be produced using any method known in the art, including
- mouse monoclonal antibodies While the invention is demonstrated using mouse monoclonal antibodies, the invention is not so limited; in 30 fact, human antibodies can be used and may prove to be preferable. Such antibodies can be obtained by using human hybridomas (Cote et al., 1983, Proc. Natl. Acad. Sci., 80:
- the binding assays used to characterize the specificity of the antibodies were performed by using radiolabeled antibodies (Brown et al., 1981, Proc. Natl. Acad. Sci. 78: 539-543); cultured cells (10 ) were incubated at 4'C for 30 minutes with 10 cpm of I-labeled antibody in 100 ⁇ l of heat-inactivated (30 minutes at 56*C) fetal calf serum in culture medium. After the addition of 5 ml of PBS, the cells were pelleted by centrifugation for 10 minutes at
- binding assays were carried out in an analogous fashion on cell monolayers attached to plastic culture dishes.
- Hybridoma supernatants were screened for binding to GD3 that had been isolated from melanoma tissue and attached to the surface of the wells of Falcon 3034 Microtest plates as previously described (Yeh et al., 1982, Int. J. Cancer 29: 269-275). Irrelevant gangliosides were included as controls.
- Hybridomas 2B2 and IF4 were derived from one hybridization, and hybridoma MG21, from a different one. They were cloned twice by limiting dilution; all make antibodies that are IgG3 according to gel diffusion.
- Antibodies were affinity-purified on a column of staphylococcal protein A covalently linked to Sepharose CL-4B (Pharmacia) by elution with 0.1 M citrate buffer, pH 3.5 or 4.5 (Brown et al., 1981, J. Immunol. 127: 539-546).
- Antibody specificity for melanoma was established by binding assays with cultured cells, as published for antibody 4.2. (Yeh et al., 1982, Int. J. Cancer 29: 269-275; Nudelman et al., 1982, J. Biol. Chem. 257: 12752-12756).
- the L6 monoclonal antibody was prepared as previously described in copending U.S. Application Serial No.
- Monoclonal antibodies were produced by immunizing three-month-old BALB/c mice with explanted cells from a human adenocarcinoma of the lung, 2981.
- the immunization was performed by injecting the mice intraperitoneally 4 times with approximately 10 cells.
- Three days after the .last immunization the spleens were removed, suspended in culture medium and fused with NS-1 mouse myeloma cells (Kohler and Milstein, 1975, Nature 256: 495-497). The mixtures were seeded to form low density cultures originating from single fused cells (clones) ; the techniques used for the hybridization have been previously described by Yeh et al. , (1982, Int. J. Cancer 29: 269-275).
- Hybridomas which produced antibodies binding to the cell membrane extracts were cloned, expanded in vitro, and further tested for antibody specificity. This testing was carried out by using an immunohistological technique
- Antibodies secreted into the ascites were.purified on protein A Sepharose (Ey et al., 1979, Im unochemistry, 15: 429-436) or by gel filtration in Sephacryl S-300. Purified antibodies were used for further characterization which included additional specificity tests by immunohistology, binding assays on intact cells to determine which antibodies bound to the cell surface, and by radioimmunoprecipitation tests.
- Monoclonal antibody L6 was produced from the corresponding hybridoma as described above.
- the present invention provides for combination therapy comprising treatment with anti-tumor antibody as well as treatment with a standard chemotherapy regimen.
- chemotherapy is administered concurrently with or, more preferably, subsequent to antibody therapy.
- the antibodies utilized in the invention are preferably anti-glycolipid antibodies.
- it is desirable to utilize whole antibody molecules whereas in alternative embodiments it will be desirable to use fragments of antibody molecules including but not limited to Fv, F(ab) and F(ab) 2 fragments.
- fragments can bind to tumor cells and render said cells more susceptible to chemotherapeutic agents while minimizing immune functions related to the Fc region of the antibody molecule and minimizing the generation of an immune response directed at a heterologous Fc region.
- the chemotherapeutic regimens utilized according to the invention include any regimen believed to be suitable for the treatment of a patient's malignancy. Different malignancies can require the use of specific anti-tumor antibodies and specific chemotherapy regimens, which will be determined on a patient to patient basis.
- the present invention relates to any malignant condition, including, but not limited to, adenocarcinomas such as breast carcinoma and colon carcinoma, non-small cell lung carcinoma, leukemia, lymphoma and neuroectoderm derived tumors including melanoma, astrocytoma and glioblastoma.
- the melanoma patient discussed in Section 7 showed complete remission of extracranial tumors but died from an intracranial metastasis which did not respond to treatment. This lack of response of the brain metastasis may be explained by a failure of antibody to penetrate the blood-brain barrier. According to the invention it is desirable to ensure that the anti-tumor antibody is capable of contacting its tumor cell target.
- K. L. is a 46 year old white female who had a lumpectomy and axillary dissection in 1985 for Stage I, estrogen receptor negative breast cancer. She received local radiotherapy post operatively. She relapsed two years later with a nodule in the left axilla outside the radiation field. She received six months of chemotherapy with adria ycin, 5- fluorouracil, and cyclophosphamide (FAC) . Five months later she relapsed with extensive disease in the remaining breast. She had a mastectomy, but again relapsed within three months. She was treated with Vinblastine/Mitomycin C but had progressive disease on her left chest wall. Because this patient displayed broad spectrum drug resistance and developed a rapid recurrence, her physician felt that additional chemotherapy was unlikely to be successful. The patient was referred for alternative treatments.
- FAC cyclophosphamide
- the patient was seen six weeks later and at that time, she had had a complete clearing of the disease from her chest wall. She was determined to be in a complete remission at that time. She was seen again ten weeks later, and continued to be in a complete remission.
- a BREAST CANCER PATIENT PREVIOUSLY RESPONSIVE TO ANTIBODY THERAPY BUT IN RELAPSE ACHIEVED COMPLETE REMISSION AFTER COMBINATION THERAPY M.G. is a 39 year old white female who was diagnosed as having inflammatory breast cancer. She was initially treated with cyclophosphamide/Adriamycin/tamoxifan/Premarinmethotrexate/5-
- the patient received murine monoclonal antibody L6.
- C. H. is a 65 year old white male who had a primary melanoma in his right middle calf. He developed recurrence
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cell Biology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Mycology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/527,227 US5165922A (en) | 1990-05-22 | 1990-05-22 | Synergistic tumor therapy with combinations of biologically active anti-tumor antibodies and chemotherapy |
US527227 | 1990-05-22 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0575321A4 EP0575321A4 (de) | 1993-07-12 |
EP0575321A1 true EP0575321A1 (de) | 1993-12-29 |
Family
ID=24100637
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP91910573A Withdrawn EP0575321A1 (de) | 1990-05-22 | 1991-05-17 | Synergistische Tumortherapie durch Kombinationen von Biologisch-aktiven anti-Tumor Antikörpern und Chemo Therapie |
Country Status (7)
Country | Link |
---|---|
US (1) | US5165922A (de) |
EP (1) | EP0575321A1 (de) |
JP (1) | JPH05508630A (de) |
CA (1) | CA2083391A1 (de) |
HU (1) | HUT63340A (de) |
WO (1) | WO1991017770A1 (de) |
ZA (1) | ZA913879B (de) |
Families Citing this family (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6733752B1 (en) * | 1994-03-30 | 2004-05-11 | The Trustees Of The University Of Pennsylvania | Prevention of tumors with monoclonal antibodies against neu |
US20030180290A1 (en) * | 1995-06-07 | 2003-09-25 | Idec Pharmaceuticals Corporation | Anti-CD80 antibody having ADCC activity for ADCC mediated killing of B cell lymphoma cells alone or in combination with other therapies |
NZ332588A (en) * | 1996-05-15 | 2000-11-24 | Altarex Inc | Cancer antigens CA125 (multiple epitote) recognised by OC125, M11, B43.13, B27.1, where B43.13 is used as a binding agent to elicit host immune response as a vaccination method against cancer |
US20080220012A1 (en) * | 1996-05-15 | 2008-09-11 | Ragupathy Madiyalakan | Therapeutic Compositions that alter the immune response |
US7318921B2 (en) * | 1996-05-15 | 2008-01-15 | Altarex Medical Corp. | Therapeutic compositions that alter the immune response |
US20060159688A1 (en) * | 1996-05-15 | 2006-07-20 | Ragupathy Madiyalakan | Method for diagnosing efficacy of xenotypic antibody therapy |
US8038994B2 (en) * | 1996-05-15 | 2011-10-18 | Quest Pharmatech Inc. | Combination therapy for treating disease |
US5837231A (en) * | 1996-06-27 | 1998-11-17 | Regents Of The University Of Minnesota | GM-CSF administration for the treatment and prevention of recurrence of brain tumors |
US6410041B1 (en) * | 1998-04-28 | 2002-06-25 | Trustees Of Tufts College | Culturing cells in presence of amphipathic weak bases and/or cations and multiple drug resistance inhibitor containing reserpine |
EP1085905B1 (de) * | 1998-06-15 | 2010-09-08 | Quest Pharmatech Inc. | Immuntherapeutische zusammensetzung und verfahren zur behandlung von prostatakrebs |
CN1689646A (zh) * | 1998-08-11 | 2005-11-02 | 拜奥根Idec公司 | 包括施用抗-cd20抗体的b-细胞淋巴瘤联合疗法 |
CA2350064C (en) * | 1998-11-09 | 2012-05-08 | Idec Pharmaceuticals Corporation | Chimeric anti-cd20 antibody treatment of patients receiving bmt or pbsc transplants |
US7311924B2 (en) * | 1999-04-01 | 2007-12-25 | Hana Biosciences, Inc. | Compositions and methods for treating cancer |
DK1169021T3 (da) * | 1999-04-01 | 2010-01-11 | Hana Biosciences Inc | Sammensætninger og fremgangsmåder til behandling af lymfom |
US7244450B2 (en) * | 1999-04-01 | 2007-07-17 | Inex Pharmaceuticals Corporation | Compositions and methods for treating lymphoma |
US6723338B1 (en) * | 1999-04-01 | 2004-04-20 | Inex Pharmaceuticals Corporation | Compositions and methods for treating lymphoma |
US8557244B1 (en) | 1999-08-11 | 2013-10-15 | Biogen Idec Inc. | Treatment of aggressive non-Hodgkins lymphoma with anti-CD20 antibody |
US7740841B1 (en) * | 2000-01-28 | 2010-06-22 | Sunnybrook Health Science Center | Therapeutic method for reducing angiogenesis |
KR100881471B1 (ko) * | 2000-05-08 | 2009-02-05 | 셀덱스 쎄라퓨틱스, 인크. | 수상세포에 대한 인간 모노클로날 항체 |
US20030103971A1 (en) * | 2001-11-09 | 2003-06-05 | Kandasamy Hariharan | Immunoregulatory antibodies and uses thereof |
JP4463475B2 (ja) * | 2001-01-31 | 2010-05-19 | バイオジェン アイデック インコーポレイテッド | 腫瘍疾患の治療における免疫調節性抗体の使用 |
WO2002089772A1 (en) * | 2001-05-09 | 2002-11-14 | Inex Pharmaceuticals Corporation | Anti-angiogenic therapy using liposome-encapsulated chemotherapeutic agents |
AU2003223600A1 (en) * | 2002-04-11 | 2003-10-27 | Altarex Medical Corporation | Binding agents and their use in targeting tumor cells |
WO2006099175A2 (en) * | 2005-03-11 | 2006-09-21 | Euro-Celtique S.A. | Compositions comprising an anti-ca125 antibody and a cytotoxic compound and their use for the treatment of cancer |
US20090074757A1 (en) * | 2005-04-08 | 2009-03-19 | Enrico Pesenti | Antitumor Combination Comprising Substituted Acryloyl Distamycin Derivatives and Antibodies Inhibiting Growth Factors or Their Receptors |
EP2162152A2 (de) * | 2007-06-01 | 2010-03-17 | Biogen Idec MA, Inc. | Cripto-bindende moleküle |
CN101969970B (zh) | 2007-10-12 | 2014-10-15 | 西雅图基因公司 | 用抗体-药物偶联物联合治疗 |
JP6320756B2 (ja) * | 2010-12-06 | 2018-05-09 | キュア キャンサー ワールドワイド エルエルシー | 癌を治療するための化学および免疫療法を用いた癌細胞の代謝標的法 |
RU2655964C2 (ru) | 2012-11-20 | 2018-05-30 | Спектрум Фармасьютикалз, Инк. | Улучшенный способ получения инкапсулированного в липосомы винкристина для терапевтического применения |
TWI678213B (zh) | 2015-07-22 | 2019-12-01 | 美商史倍壯製藥公司 | 用於長春新鹼硫酸鹽脂質體注射之即可使用的調配物 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4693966A (en) * | 1983-03-11 | 1987-09-15 | Sloan-Kettering Institute For Cancer Research | Human monoclonal antibodies from lymphocytes of patients with malignant melanoma |
US4906562A (en) * | 1984-12-21 | 1990-03-06 | Oncogen | Monocolonal antibodies and antigen for human non-small cell lung carcinomas |
-
1990
- 1990-05-22 US US07/527,227 patent/US5165922A/en not_active Expired - Fee Related
-
1991
- 1991-05-17 EP EP91910573A patent/EP0575321A1/de not_active Withdrawn
- 1991-05-17 HU HU923628A patent/HUT63340A/hu unknown
- 1991-05-17 WO PCT/US1991/003483 patent/WO1991017770A1/en not_active Application Discontinuation
- 1991-05-17 JP JP91510236A patent/JPH05508630A/ja active Pending
- 1991-05-17 CA CA002083391A patent/CA2083391A1/en not_active Abandoned
- 1991-05-22 ZA ZA913879A patent/ZA913879B/xx unknown
Non-Patent Citations (1)
Title |
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See references of WO9117770A1 * |
Also Published As
Publication number | Publication date |
---|---|
HUT63340A (en) | 1993-08-30 |
JPH05508630A (ja) | 1993-12-02 |
CA2083391A1 (en) | 1991-11-23 |
US5165922A (en) | 1992-11-24 |
WO1991017770A1 (en) | 1991-11-28 |
HU9203628D0 (en) | 1993-04-28 |
EP0575321A4 (de) | 1993-07-12 |
ZA913879B (en) | 1992-03-25 |
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